Drug-drug interaction between repaglinide and clopidogrel: Potential risk of hypoglycaemia

HSA would like to highlight the findings of a recent study which concluded that co-administration of repaglinide and clopidogrel results in an increased systemic exposure to repaglinide, due to strong inhibition of CYP2C8 by clopidogrel acyl-β-D-glucuronide. This could in turn enhance the glucose-lowering effect of repaglinide, thereby predisposing patients to the risk of hypoglycaemia.

Repaglinide (Novonorm®, Novo Nordisk Pharma (Singapore) Pte Ltd) is an oral antidiabetic agent that has been registered locally since January 1999 for the treatment of adults with type 2 diabetes mellitus. It is approved for use as monotherapy in patients whose hyperglycaemia is inadequately controlled by lifestyle modifications or in combination with metformin in patients whose hyperglycaemia is inadequately controlled by metformin alone.

Clopidogrel (Plavix®, Sanofi-Aventis Singapore Pte Ltd) is an antiplatelet agent that has been registered locally since June 1998. It is approved for the prevention of atherothrombotic events in adults with recent myocardial infarct, recent stroke, established peripheral arterial disease or acute coronary syndrome, as well as in combination with aspirin for the prevention of atherothrombotic and thromboembolic events in selected adult patients with atrial fibrillation. Currently, there are 12 generic clopidogrel-containing products registered in Singapore.

Study findings1

In a study conducted by Tornio et al, nine healthy subjects received clopidogrel (300mg on day 1, followed by 75mg daily for 2 consecutive days) or a single dose of placebo in a crossover manner. Repaglinide was co-administered as single dose of 0.25mg on days 1 and 3 of clopidogrel treatment and on the day of placebo administration.  Co-administration of repaglinide and clopidogrel was shown to result in an increase in repaglinide systemic exposure (AUC_0-∞) by 5.1-fold and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively, when compared with placebo (p<0.001). The elimination half-life of repaglinide was also observed to be prolonged by 42% and 22%, respectively (p<0.005). The blood glucose levels of study subjects were significantly lower in both clopidogrel phases as compared to placebo, reaching a minimum concentration of 3.3 ± 0.6mmol/L, 3.9 ± 0.6mmol/L and 4.4 ± 0.5mmol/L following administration of repaglinide 1 hour after dosing with clopidogrel 300mg (day 1), clopidogrel 75mg (day 3) or placebo, respectively.

This study also identified clopidogrel acyl-β-D-glucuronide, the metabolite of clopidogrel, as a potent time-dependent inhibitor of CYP2C8 in vitro.  In view of the study findings, the study authors recommended that concomitant use of repaglinide and clopidogrel is best avoided. They also postulated that clopidogrel is likely to cause drug-drug interactions with other CYP2C8 substrates, such as montelukast, paclitaxel and pioglitazone, which warrant further clinical studies.

HSA’s advisory

To date, HSA has not received any reports of hypoglycaemia associated with the concomitant use of repaglinide and clopidogrel. HSA is working with the companies to strengthen the local package inserts of both products to include warnings and precautions with regard to the potential risk of hypoglycaemia arising from their drug-drug interaction.

Healthcare professionals are advised to consider the above safety information when prescribing repaglinide and clopidogrel together, and to monitor for signs and symptoms of hypoglycaemia in patients taking concomitant repaglinide and clopidogrel.

Healthcare professionals are encouraged to report any suspected adverse reactions of hypoglycaemia with the concomitant use of repaglinide and clopidogrel to the Vigilance and Compliance Branch of HSA.

Reference

1)    Clin Pharmacol Ther 2014; 96: 498-507